Dietary Sodium Chloride Intake Research Articles

Salt restriction for the prevention of cardiovascular disease.

Restricting the dietary intake of sodium chloride is associated with a reduction of the arterial blood pressure by approximately 4/2 mm Hg in hypertensive patients and by approximately 1/0.6 mm Hg in normotensive persons. As the cardiovascular risk is known to rise steadily with systolic blood pressure values starting from 115 mm Hg, lowering the mean blood pressure of the general population by dietary salt restriction would seem to be a practicable form of primary prevention of cardiovascular disease. Selective literature search and review. Multiple studies have shown dietary salt restriction to be associated with lower cardiovascular morbidity and mortality. The reduction of adjusted relative risk in controlled observational studies ranges from 25% over 15 years to 41% over three years. On the basis of the available studies, it seems likely that a moderate lowering of the daily intake of sodium chloride by the general population from 8 to 12 grams per day (the current value) to 5 to 6 grams per day would be a useful public health measure, with economic benefits as well. The potential risks for certain groups of individuals are foreseeable and controllable. A general reduction of dietary salt intake can only be achieved by reducing the sodium chloride content of industrially processed foods, as these account for 75% to 80% of the sodium chloride consumed daily. Aside from a general reduction of dietary salt intake, further important primary prevention measures for the general population include changes in lifestyle and in dietary habits.

Adenosine 2A Receptors and Epoxyeicosatrienoic Acids

Adenosine _2A Receptors and Epoxyeicosatrienoic Acids

Compelling evidence for salt-dependence of blood pressure from GENSALT

The concept of blood pressure salt-sensitivity refers to the interindividual difference in the blood pressure response to changes in dietary sodium chloride intake. According to Guyton's pioneer work, the phenomenon of salt-sensitivity implies the existence of interindividual differences in the

Dietary sodium chloride intake independently predicts the degree of hyperchloremic metabolic acidosis in healthy humans consuming a net acid-producing diet

We previously demonstrated that typical American net acid-producing diets predict a low-grade metabolic acidosis of severity proportional to the diet net acid load as indexed by the steady-state renal net acid excretion rate (NAE). We now investigate whether a sodium (Na) chloride (Cl) containing diet likewise associates with a low-grade metabolic acidosis of severity proportional to the sodium chloride content of the diet as indexed by the steady-state Na and Cl excretion rates. In the steady-state preintervention periods of our previously reported studies comprising 77 healthy subjects, we averaged in each subject three to six values of blood hydrogen ion concentration ([H]b), plasma bicarbonate concentration ([HCO(3)(-)]p), the partial pressure of carbon dioxide (Pco(2)), the urinary excretion rates of Na, Cl, NAE, and renal function as measured by creatinine clearance (CrCl), and performed multivariate analyses. Dietary Cl strongly correlated positively with dietary Na (P < 0.001) and was an independent negative predictor of [HCO(3)(-)]p after adjustment for diet net acid load, Pco(2) and CrCl, and positive and negative predictors, respectively, of [H]b and [HCO(3)(-)]p after adjustment for diet acid load and Pco(2). These data provide the first evidence that, in healthy humans, the diet loads of NaCl and net acid independently predict systemic acid-base status, with increasing degrees of low-grade hyperchloremic metabolic acidosis as the loads increase. Assuming a causal relationship, over their respective ranges of variation, NaCl has approximately 50-100% of the acidosis-producing effect of the diet net acid load.

Clinical Significance of Serum Oxidized Low-Density Lipoprotein/β2-Glycoprotein I Complexes in Patients with Chronic Renal Diseases

Background: Peroxidation of low-density lipoprotein (LDL) plays an important role in the development of dyslipidemias associated with the progression of chronic renal disorders. We recently reported [J Lipid Res 2001;42:697, 2002;43:1486, 2003;44:716] that oxidized LDL (oxLDL) interacts with an endogenous plasma protein, β₂-glycoprotein I (β₂GPI), via specific ligands. In the present study, the prevalence and clinical significance of oxLDL/β₂GPI complexes were evaluated in patients with chronic renal disorders. Methods: Serum levels of oxLDL/β₂GPI complexes were measured by ELISA in patients with chronic renal disease and their association with clinical manifestations was assessed. Results: The serum levels of oxLDL/β₂GPI complexes were significantly higher in patients with chronic renal failure (CRF), chronic nephritis (CN) and diabetes mellitus than those in healthy individuals. The presence of complexes in patients with CN was significantly associated with high dietary protein and sodium chloride intake, but not with lipid metabolic parameters. Malondialdehyde-modified LDL was significantly associated with total cholesterol and LDL cholesterol in all patient groups, but did not correlate with renal function parameters. Conclusions: Serum oxLDL/β₂GPI complexes, generated by oxidative stress and associated with high dietary protein and salt intake, might be a novel risk factor and a diagnostic marker for the development of chronic renal diseases, especially IgA nephropathy.

Sodium sensitivity in young adults with high resting end-tidal CO2.

Previous research with normotensive adults aged over 40 years ('older') found that sensitivity of blood pressure of subjects with high resting end-tidal partial pressures of CO2 to high sodium intake was greater than normal. To test the hypothesis that the lesser sensitivity of blood pressure of young normotensive adults to high sodium intake is also a function of resting end-tidal partial pressure of CO2. Forty-eight Caucasian men and women (age 28.5 +/- 1.4 years) had a lower than normal dietary intake of sodium chloride for 4 days, and then ingested sodium chloride capsules for 7 days (an additional 190 mmol/day sodium chloride). Resting end-tidal partial pressure of CO2 and blood pressure, and 24 h ambulatory blood pressure, were measured before and after the high-sodium diet. Overnight urine samples were collected before and after the high-sodium diet to determine dietary compliance, and to assess changes in urinary excretion of endogenous digitalis-like factors (a ouabain-like factor, and a marinobufagenin-like factor) that covary with plasma volume. Subjects with high end-tidal partial pressures of CO2 had lower resting heart rates and lower urinary excretion of ouabain-like factor before sodium loading. Sodium loading decreased mean partial pressure of CO2 (by 0.8 +/- 0.2 mmHg) and increased only ambulatory systolic blood pressure (by 2.1 +/- 0.8 mmHg) for the whole group. However, the changes in resting systolic (r = 0.32, P < 0.025) and diastolic (r = 0.36, P < 0.01) blood pressures and in 24 h systolic (r = 0.28, P < 0.05) blood pressure after sodium loading were all positive functions of individual resting end-tidal partial pressures of CO2. Sodium loading increased urinary excretion of marinobufagenin-like factor (by 1.78 +/- 0.88 nmol) and the magnitude of the individual increase was a function of end-tidal partial pressure of CO2. The results indicate that a high resting partial pressure of CO2 augments the effects of high sodium intake on plasma volume, levels of endogenous digitalis-like factors, and blood pressure in young normotensive humans.

High end tidal CO2 association with blood pressure response to sodium loading in older adults.

To test the hypothesis that blood pressure of older adults with high resting end tidal CO2 (PETCO2) is sensitive to high dietary intake of sodium chloride. Forty-four Caucasian men and women, aged 41-79 years (mean +/- SEM 55.5 +/- 1.4), restricted their dietary intake of sodium chloride for 11 days and ingested sodium chloride capsules (an additional 190 mmol sodium/day) during the last seven of those days. On days 1, 4 and 11, resting PETCO2 and blood pressure were monitored for 25 min in the laboratory, followed by ambulatory blood pressure monitoring in the natural environment for 24 h. Overnight urine samples were obtained at days 4 and 11 to estimate excretion of sodium and of an endogenous digitalis-like factor (EDLF) that is sensitive to changes in plasma volume. Individual resting PETCO2 remained stable within and between laboratory monitoring sessions and was correlated with urinary excretion of the endogenous digitalis-like factor, both before and after the period of high sodium intake. The high-sodium diet was associated with increased urinary sodium excretion and body weight in all quartiles of PETCO2. The high-sodium diet produced significant increases in resting and in 24 h systolic blood pressures in the upper two quartiles of the PETCO2 distribution, and significant increases in resting and in 24 h diastolic blood pressures in the highest PETCO2 quartile only. These findings indicate blood pressure sensitivity to sodium loading is differentially associated with high resting PETCO2 in older adults. A high PETCO2 may be an index of a dynamic steady state that influences sodium transport mechanisms.

Cosegregation of the endothelin-3 locus with blood pressure and relative heart weight in inbred Dahl rats

To determine whether the endothelin-1 or endothelin-3 genes are genetically linked with blood pressure and relative heart weight in segregating rat populations, in the context of an elevated dietary sodium chloride intake. Endothelin-1 and endothelin-3 genotypes of rats in segregating populations, derived from crosses of Dahl salt-sensitive (SS/Jr) rats with contrasting inbred strains, including Lewis rats, spontaneously hypertensive rats and Dahl salt-resistant (SR/Jr) rats, were determined using restriction fragment length polymorphisms. Segregating populations were fed a high (8%)-sodium chloride diet. Linkage of genotype with blood pressure or relative heart weight was determined by analysis of variance. Chromosomal location of the rat endothelin-3 gene was determined by genotyping a panel of recombinant inbred strains. Two alleles for the endothelin-1 gene and three alleles for the endothelin-3 gene were identified. The endothelin-1 locus did not cosegregate with blood pressure or relative heart weight. The endothelin-3 locus cosegregated with blood pressure and relative heart weight in an SS/Jr x F1 (SS/Jr x SR/Jr) population, but not in populations containing a higher percentage of genes from the SR/Jr strain. The endothelin-3 and seminal vesicle protein-1 loci were linked and located on rat chromosome 3. The endothelin-3 gene is, or is linked to, a locus on chromosome 3 that regulates blood pressure and relative heart weight in inbred Dahl rats, and these effects were strongly dependent on the genetic background.

Improvement of cardiovascular effects of metoprolol by replacement of common salt with a potassium- and magnesium-enriched salt alternative.

1. The influence of sodium chloride (NaCl)-enrichment of the diet (6% of the dry weight) and that of a novel sodium-reduced, potassium-, magnesium-, and L-lysine-enriched salt alternative on the cardiovascular effects of the beta 1-adrenoceptor blocking drug, metoprolol, was studied in stroke-prone spontaneously hypertensive rats. 2. Increased dietary sodium chloride intake produced a marked rise in blood pressure and induced left ventricular and renal hypertrophy. By contrast, the salt alternative did not increase blood pressure and caused remarkably less cardiac and renal hypertrophy than did sodium chloride. 3. Metoprolol treatment at a daily dose of 250 mg kg-1 lowered blood pressure and decreased left ventricular hypertrophy index during the control diet. Sodium chloride-enrichment blocked the antihypertensive effect of metoprolol, while a partial protective effect on left ventricular and renal hypertrophy persisted. In the presence of the salt alternative-enrichment both at the level of 6% and 10.5% (corresponding to a NaCl level of 6%), metoprolol was fully able to exert its beneficial cardiovascular and renal effects. 4. Both salt supplementations, irrespective of metoprolol treatment, induced a 3 to 4 fold increase in the urinary excretion of calcium. There was a linear correlation between the urinary excretions of sodium and calcium. The urinary excretion of magnesium rose by 90% and that of potassium by 110% in the salt alternative group. 6. Our findings suggest that replacement of common salt by a potassium-, and magnesium-enriched salt alternative in the diet produces beneficial cardiovascular effects and improves the antihypertensive efficacy of metoprolol in stroke-prone spontaneously hypertensive rats. Increased intake of potassium and/or magnesium and L-lysine from the salt alternative is involved in the beneficial effects of the salt alternative. The NaCl-induced myocardial and renal hypertrophies appear to be partially mediated by Beta-adrenoceptor activation.

Effect of dietary potassium chloride in borderline hypertensive rats.

The borderline hypertensive rat is the first filial offspring of the spontaneously hypertensive rat and the Wistar-Kyoto rat. With increased dietary sodium chloride intake, the borderline hypertensive rat develops hypertension and exaggerated cardiovascular and renal responses to acute environmental stress, similar to those observed in the hypertensive spontaneously hypertensive rat parent. In other models of sodium chloride-sensitive hypertension with different genetic background (Dahl rat), dietary potassium chloride supplementation protects against the development of hypertension, increased sympathetic nervous system activity, and exaggerated responses to acute environmental stress. This investigation sought to determine whether the dietary sodium chloride-induced development of both the hypertension and the exaggerated responses to acute environmental stress could be reversed or prevented by increased dietary potassium chloride intake. Dietary potassium chloride intake was increased with a 1% potassium chloride drinking solution either after 12 wk of 8% sodium chloride intake (reversal) or concomitant with the onset of 12 wk of 8% sodium chloride intake (prevention). An increase in dietary potassium chloride intake did not reverse or prevent the development of either the hypertension or the exaggerated cardiovascular and renal responses to acute environmental stress in borderline hypertensive rats fed 8% sodium chloride. It is concluded that the difference in genetic background between borderline hypertensive rats and other models of sodium chloride-sensitive hypertension is an important determinant of the protective effect of dietary potassium chloride supplementation.

Role of chloride in angiotensin II-induced salt-sensitive hypertension.

The present study investigated the effect of the anion accompanying sodium on the development of angiotensin II-induced hypertension in rats and the role of the sympathetic nervous system and extracellular fluid volume in its mechanism. Hypertension was induced by intraperitoneal infusion of angiotensin II (125 ng/min) for 12 days via miniosmotic pump. High dietary intake of sodium chloride significantly augmented the angiotensin II-induced hypertension (mean blood pressure on day 13, 165 +/- 6 versus 142 +/- 6 mm Hg, p less than 0.05), but equimolar sodium loading provided as sodium citrate failed to enhance angiotensin II hypertension (140 +/- 6 mm Hg). Plasma norepinephrine concentration in the conscious, resting state increased with sodium chloride loading in angiotensin II-infused rats (594 +/- 42 versus 312 +/- 37 pg/ml, p less than 0.01), but it remained unchanged with sodium citrate loading (324 +/- 23 pg/ml). Correspondingly, maximum response to hexamethonium bromide, a ganglion blocker, was greater in sodium chloride-loaded angiotensin II rats (77.7 +/- 4.6 mm Hg) than that in angiotensin II (59.7 +/- 5.1 mm Hg) or in sodium citrate-loaded angiotensin II (57.7 +/- 4.2 mm Hg) rats. Moreover, extracellular fluid volume, measured as Na2(35)SO4 space, increased in sodium chloride-loaded angiotensin II rats (427 +/- 18 ml/kg body wt) as compared with that in angiotensin II rats (375 +/- 15 ml/kg body wt) but not when compared with volume in sodium citrate-loaded angiotensin II (389 +/- 7 ml/kg body wt) rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of Chloride in the Development of Salt-Induced Angiotensin II Hypertension in Rats

This study attempted to evaluate the effect of anion associated with sodium loading on the development of angiotensin II (AII)-induced hypertension in rats. Hypertension was induced by intraperitoneal infusion of AII(125 ng/min) for 12 days via miniosmotic pump (systolic blood pressure on day 12, 143 +/- 3 mm Hg). High dietary intake of sodium chloride significantly augmented the AII-induced hypertension (systolic blood pressure on day 12, 166 +/- 4 mm Hg), but equimolar sodium loading provided as sodium citrate failed to enhance AII hypertension (systolic blood pressure on day 12, 136 +/- 8 mm Hg). Thus, the data suggest that the full expression of salt (NaCl) sensitivity in AII hypertension depends on high dietary intake of both sodium and chloride.

Research and policy directions. Salt and blood pressure.

The relation between dietary intake of sodium chloride and blood pressure levels remains controversial. The critical questions concern whether there is a susceptible subgroup at risk of elevated blood pressure because of sodium chloride consumption. If there is such a subgroup, what is its size and how can it be identified? Further clinical trials are needed to determine the long-term effects of sodium chloride reduction on blood pressure. The risk of disease, including stroke and coronary heart disease, is linear with blood pressure levels. A small change in blood pressure can have a relatively large impact on disease, even within the normal range of blood pressure.

Modification of dietary sodium chloride intake: effects on diuresis and endogenous dopamine activity in the rat

Modification of dietary sodium chloride intake: effects on diuresis and endogenous dopamine activity in the rat

Modulation of mouse renin gene expression by dietary sodium chloride intake in one-gene, two-gene and transgenic animals.

We have studied the effect of dietary NaCl loading on renin gene expression in one-gene, two-gene and transgenic mouse strains. By Northern blotting, we found an approximate twofold reduction in renin messenger (m) RNA in the kidneys of high-NaCl-treated compared with low-NaCl-treated animals. Using an RNase-protection assay designed to discriminate between the different renin gene transcripts, we have shown that renin mRNAs derived from the Ren-1C gene of one-gene strains and the Ren-1D and Ren-2 genes of two-gene animals are all NaCl-responsive. Renin mRNA derived from a 19 kilobase Ren-1D transgene is also NaCl-responsive.

On the mechanism by which chloride corrects metabolic alkalosis in man

To determine whether administration of chloride corrects chloride-depletion metabolic alkalosis (CDA) by correction of plasma volume contraction and restoration of glomerular filtration rate or by an independent effect of chloride repletion, CDA was produced in normal men by the administration of furosemide and maintained by restriction of dietary sodium chloride intake. Negative sodium balance (−112 ± 16 meq) and reduced plasma volume (2.53 versus 2.93 liters, p <0.05) developed. The cumulative chloride deficit of 271 ± 16 meq was then repleted by oral potassium chloride (267 ± 19 meq) over 36 hours with continued serial measurements of glomerular filtration rate, effective renal plasma flow, plasma volume, body weight, and plasma renin and aldosterone levels. CDA was corrected, even though body weight, plasma volume, glomerular filtration rate, and renal plasma flow all remained reduced and plasma aldosterone was elevated; urinary bicarbonate excretion increased during correction. Administration of an identical potassium chloride load to similarly sodium-depleted but not chloride-depleted normal subjects produced no change in acid-base status. It is concluded that chloride repletion can correct CDA by a renal mechanism without restoring plasma volume or glomerular filtration rate or by altering sodium avidity.

Response of atrial natriuretic peptide in plasma and urine to changes in dietary intake of sodium chloride in man.

Plasma concentration and urinary excretion of immunoreactive human atrial natriuretic peptide (ir-hANP), aldosterone, and vasopressin were measured, and renal function and blood pressure were determined in six healthy male subjects in three periods of different sodium intake: the control (172 mEq/day), low (20 mEq/day), and high (285 mEq/day) sodium period. Both plasma concentration and urinary excretion of ir-hANP increased significantly in the high sodium period but did not change between the control and low sodium periods. On the contrary, aldosterone increased and vasopressin decreased in the low sodium period but did not change between the control and high sodium periods. These results may point out the reciprocal action of both endocrine systems. The glomerular filtration rate changed in parallel with sodium intake whereas the fractional excretion of sodium decreased only in the low sodium period, probably reflecting the action of aldosterone. It is concluded from these results that the atrial peptide may be an important component in the regulation of body fluid in the high sodium loading of physiological range but its action may be limited to the control of glomerular filtration rate.

Lithium clearance in man: effects of dietary salt intake, acute changes in extracellular fluid volume, amiloride and frusemide.

1. The effects of amiloride and frusemide on lithium clearance were studied during changes in dietary sodium chloride intake and during infusion of 0.9% NaCl in normal human volunteers. 2. Lithium and fractional lithium clearances were less on the low than on the high salt diet. Values for the medium salt diet were intermediate. Acute extracellular fluid volume expansion with 0.9% NaCl infusion and extracellular fluid volume contraction 3-4 h after intravenous frusemide caused lithium and fractional lithium clearances to increase and decrease respectively. 3. Amiloride caused small changes in lithium and fractional lithium clearances on a low salt diet, but was without effect when salt intake was medium or high. 4. Increases in lithium clearance occurred immediately after frusemide irrespective of dietary salt intake and in subjects infused with 0.9% NaCl. Only in salt-depleted subjects did frusemide cause a substantial increase in fractional lithium clearance. Changes induced under other circumstances were small. 5. It is concluded that the lithium clearance method for assessment of proximal tubule salt and water reabsorption can be used with some degree of confidence in certain circumstances (medium and high salt intake as well as in acute volume expansion) but may not be reliable when dietary salt intake is low.

Effect of dietary sodium chloride and posture on plasma immunoreactive atrial natriuretic peptide concentrations in man.

The effect of changes of dietary sodium chloride intake and posture on plasma atrial natriuretic peptide concentration and renal function was studied in 11 normal human volunteers. Plasma atrial natriuretic peptide concentration was higher in the upright posture on a high than it was on a medium or low salt diet. On the medium and high but not on the low salt diet the concentration increased significantly on adoption of the supine posture. Creatinine, sodium, lithium and fractional lithium clearances, fractional distal sodium excretion and total distal water and sodium reabsorption, which were estimated by the lithium clearance technique, were significantly higher on the high than on the low salt diet. The medium salt intake gave intermediate values. Heart rate while upright was significantly higher on the low than on either the medium or the high salt diets. Systolic blood pressure was unaffected by salt intake. Diastolic blood pressure in the supine position was significantly higher on the low than on the medium or high salt diets. Both plasma noradrenaline concentrations and plasma renin activity were significantly higher on the low than on the high salt diet. Values on the medium salt intake were intermediate. Plasma concentrations of both hormones were higher in the upright than in the supine posture on all three salt intakes. The data are consistent with the hypothesis that atrial natriuretic peptide contributes to the cardiovascular and renal adjustments to changes in dietary sodium chloride, and the possible role of the peptide is discussed.

Dietary intake of sodium chloride in the rat influences [3H]nitrendipine binding to adrenal glomerulosa cell membranes but does not alter binding to vascular smooth muscle membranes.

Angiotensin II-stimulated secretion by adrenal glomerulosa cells and contraction by vascular smooth muscle (VSM) are dependent on calcium influx through membrane calcium channels. We have examined the hypothesis that the altered responsiveness of adrenal glomerulosa cells and VSM to angiotensin II during NaCl restriction may be associated with a change in membrane calcium channel number. To test this hypothesis, female rats were placed on a high or low NaCl diet. On the 14th day, membranes were prepared from the zona glomerulosa, aorta, mesenteric artery, and uterus. [3H]Nitrendipine binding was used to monitor calcium channel number. The [3H]nitrendipine binding capacity was observed to be higher in the zona glomerulosa during NaCl restriction than during high NaCl intake (83 +/- 18 vs. 49 +/- 9 fmol/mg protein, P less than 0.025, n = 6 paired experiments). The binding capacities of [3H]nitrendipine on the low and high NaCl diet were similar in the mesenteric artery (10 +/- 1 vs. 9 +/- 1 fmol/mg protein, n = 8), aorta (33 +/- 5 vs. 35 +/- 8 fmol/mg protein, n = 5), or uterus (87 +/- 15 vs. 85 +/- 16 fmol/mg protein, n = 4), respectively. The dissociation constants of [3H]nitrendipine binding did not differ on a low or high NaCl intake in the zona glomerulosa (0.84 +/- .12 vs. 0.79 +/- .10 nM), mesenteric artery (0.82 +/- .06 vs. 83 +/- .05 nM), aorta (0.90 +/- .11 vs. 0.92 +/- .12 nM), or uterus (0.55 +/- .12 vs. 0.56 +/- .10 nM), respectively. We conclude that the blunted response of VSM to angiotensin II during NaCl restriction is best explained by the previously reported lower number of angiotensin II receptors since calcium channel number does not change. In the adrenal glomerulosa cell, NaCl restriction is associated with a higher number of membrane calcium channels and angiotensin II receptors. The increase in calcium channel number may reflect the influence of an unknown factor(s) believed to be necessary for the full expression of the adrenal glomerulosa cell response to NaCl restriction.